tbuckley/cabot-search huggingface dataset:
CTIM-06. A PHASE 2 STUDY OF A NOVEL IMMUNOTHERAPY SL-701 IN ADULTS WITH RECURRENT GLIOBLASTOMA: EXPLORING THE PROGNOSTIC VALUE OF TREATMENT-INDUCED CD8+CD57+ T-CELLS AS A MARKER FOR SURVIVAL
Authors: David Peereboom, Ross Lindsay, Michael Badruddoja, L Burt Nabors, Priya Kumthekar, Frank Lieberman, David Schiff, Jonathan Sherman, Nicholas Butowski, Erin Dunbar, Karen Fink, Fabio Iwamoto, Christopher Moertel, Michael Schulder, Tobias Walbert, Pratip Chattopadhyay, Nassir Habboubi, Krzysztof Grzegorzewski, Christopher Brooks, David Reardon
Journal: Neuro-Oncology (2023)

Abstract Recurrent glioblastoma (GBM) remains a challenging disease with limited therapeutic options and poor prognosis. SL-701 is a novel immunotherapy composed of synthetic peptides designed to elicit an anti-tumor immune response against the overexpressed GBM antigens IL-13Rα2, ephrinA2, and survivin. In this study, we present updated findings from a phase 2 clinical trial (NCT02078648) evaluating SL-701+poly-ICLC+bevacizumab, where the 12-month overall survival (OS) was 50%. Using high-parameter flow cytometry, we compared the quality of the treatment induced T-cell response in patients with an OS &amp;lt; 12m (n = 15) versus OS &amp;gt;12m (n = 12). Among the patients assessed, 89% exhibited heterogeneous T-cell responses against SL-701, with no discernible correlation between the response to a specific peptide and survival. Consequently, we focused on identifying other characteristics of the pan-SL701-specific T-cell response with an association to survival. Assessing all time points collected, patients with an OS &amp;gt;12m generated a significantly higher frequency of SL-701-specific CD8 T-cells (79% increase, P &amp;lt; 0.005) and a lower frequency of CD4+ T-cells (36% decrease, P &amp;lt; 0.05) compared to patients with a lower OS. Moreover, the ratio of CD8:CD4 T-cells was 2-fold higher in patients with an OS &amp;gt;12m indicating a CD8-enriched response, whereas patients with an OS &amp;lt; 12m had a lower ratio of CD8:CD4 associated with CD4 enriched responses. Notably, patients with an OS &amp;gt;12m, expressed CD57 (identifying highly cytotoxic, differentiated memory T-cells) on 40% of their T-cells compared to 18% in patients with an OS &amp;lt; 12m (P &amp;lt; 0.05). Furthermore, the ratio of SL-701 specific CD57:CD107A expressing cells trended 20% lower in patients with an OS &amp;gt;12m, indicative of a replicating, cytotoxic T-cell response that is not terminally differentiated. These qualitative differences in the immune response, detectable as early as week 8 post treatment, may serve as biomarkers for monitoring and predicting survival. Deep sequencing of SL-701-specific T-cells is planned.
BIOM-29. FIBRONECTIN TYPE III DOMAIN CONTAINING 3B AS PROGNOSTIC BIOMARKER AND REGULATORY TARGET FOR MALIGNANT BRAIN TUMOR
Authors: Hyukjun Kwon, Minji Yun, Minji Bang, Jungsul Lee, Hae Young Ko, Kyuha Chong
Journal: Neuro-Oncology (2023)

Abstract Malignant brain tumor (MBT) is an aggressive tumor with high drug-resistance and recurrence rates. Using ‘Oncopression’ big data analysis, we found that a fibronectin-related protein, fibronectin type III domain containing 3B (FNDC3B), was specifically overexpressed in brain tumor patients and conducted a pilot and mechanism study on the role of FNDC3B in MBT. We evaluated the functional significance of FNDC3B in MBT using FNDC3B specific siRNA and performing cell viability assay, real-time qPCR, Western blot, 3D-invasion assay, and wound healing assay. Furthermore, using proteome profiler human phospho-kinase arrays, we investigated the correlated signaling which activated while FNDC3B-mediated MBT cell progression. We found that down-regulation of FNDC3B decreased tumor cell proliferation, migratory and invasiveness properties as well as stemness phenotype which are hallmarks of cancer progression. Furthermore, we demonstrate that PI3K/AKT signaling pathways were involved mainly in FNDC3B-related tumor growth and mesenchymal phenotypes. Although follow-up studies are necessary, the results of this study suggest that FNDC3B is worth investigating as a novel alternative diagnostic and therapeutic target candidate for MBT.
DDEL-15. EXPLORING THE USE OF MACHINE LEARNING TO PREDICT BLOOD BRAIN BARRIER PERMEABILITY OF DRUG MOLECULES
Authors: Megan Amber Lim, Wael Hassaneen Mostafa
Journal: Neuro-Oncology (2023)

Abstract The blood-brain barrier (BBB) is a selective boundary of the central nervous system (CNS) that plays a critical role in protecting the brain microenvironment by allowing passage of certain molecules. Clinical experiments accurately determine which chemotherapy drugs effectively cross the BBB to reach the tumor site but are also time consuming and labor intensive. Machine learning offers the ability to rapidly screen large datasets of drug molecules and assess their potential for CNS therapeutic effect. The goal of this study is to compare the performance across machine learning, deep learning, and transfer learning methods in predicting BBB permeability on public drug datasets. The dataset used for training and validation was composed of 7,807 compounds compiled from 50 published resources. The machine and deep learning methods used in this study included support vector machines (SVMs), deep neural networks (DNNs), and graph convolutional neural networks (GCNNs). For transfer learning, we first trained DNN models to a single quantum chemical property before appending neural network layers and retraining to the new task of BBB permeability. The prediction accuracies on the validation set for SVM, DNN, GCNN, transfer learning of polarizability, and transfer learning of dipole moment were 82.33%, 83.09%, 87.14%, 76.89%, and 70.23%, respectively. Overall, the results indicate that GCNN was the best performing model. This highlights GCNNs ability to learn the molecular features most relevant to the predictive task in the first stage of the algorithm. Future work entails expanding the set of input features to include key chemical and structural information such as the presence or absence of certain functional groups as well as training more transfer learning models to other quantum chemical properties. This study further motivates the predictive capability of machine learning methods in identifying drug compounds with potential CNS-activity.
RADT-13. A BIOLOGIC EQUIVALENT DOSE COMPARISON BETWEEN RADIOSURGERY AND COLLAGEN TILE BRACHYTHERAPY FOR POST-OPERATIVE TREATMENT OF A BRAIN METASTASIS RESECTION CAVITY
Authors: Adam Turner, Michael Garcia
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Recurrence of a previously irradiated brain metastasis represents a challenging clinical scenario. Repeat radiosurgery results in sub-optimal local control (LC). Two independently published prospective cohort studies demonstrated durable LC in this setting with collagen tile brachytherapy (CTBT), a novel Cesium-131 carrier. Here we compare biologically equivalent dosimetric parameters of CTBT to radiosurgery to understand dose metrics that may underlie durable LC from CTBT. METHODS A patient was selected from the multi-institutional prospective CTBT registry (NCT04427384) with a brain metastasis resection cavity near brainstem. Planning was performed for radiosurgery (30Gy in 5 fractions, BED of 48Gy) and CTBT (Cs-131, activity of 3.5U). To directly compare dosimetric parameters between radiosurgery and CTBT, biologic equivalent doses (BED) were calculated for brainstem(α/β of 3, BED3) and oncologically at-risk tissue(α/β of 10, BED10). TG101 brainstem dose-constraints were referenced, and respective BED were calculated. RESULTS The resection cavity was 4mm away from brainstem and contained 7 CTBT tiles (28 Cs131 seeds). Gradient index (GI) (24Gy BED10 volume/48Gy BED10 volume) was 3.8 for radiosurgery and 2.2 for CTBT. Conformality index (CI) (48Gy BED10 volume/CTV volume) was 1.2 for radiosurgery and 2.6 for CTBT. BED10 to 90% of the cavity wall (2mm rim around the resection cavity) was 49.6Gy for radiosurgery and 92.6Gy for CTBT. BED3 dose limit goals (max dose 31Gy in 5 fractions, BED3 95.1Gy and threshold dose 23Gy in 5 fractions, BED3 of 58.3Gy to 0.5cc) were met for both radiosurgery and CTBT. CONCLUSION BED comparisons demonstrate that CTBT leads to higher CI, lower GI, and higher dose to the cavity wall than radiosurgery while meeting BED3 dose limit goals to an adjacent organ at risk. These dose characteristics might underlie durable LC seen in the recurrent brain metastasis setting, though larger scale analyses are being performed with with clinical outcomes on NCT04427384.
CCRG-07. GOLD NANOPARTICLES DEMONSTRATE FAVORABLE EFFECTS ON THE BEHAVIOR OF MESENCHYMAL STEM CELLS, THEREBY AUGMENTING THEIR OVERALL BIOLOGICAL PERFORMANCE
Authors: Chiung-Chyi Shen, Ruei-Hong Lin, Yi-Chin Yang, Huey-Shan Hung
Journal: Neuro-Oncology (2023)

Abstract Gold nanoparticles (AuNPs) have been extensively studied for their interaction with cells, particularly mesenchymal stem cells (MSCs), and their potential to influence various cellular behaviors such as proliferation and differentiation. In this research, AuNP solutions at concentrations ranging from 1.25 to 10 ppm were prepared to investigate their biocompatibility. The presence of AuNPs was confirmed using ultraviolet-visible spectroscopy, while Dynamic Light Scattering assay characterized their size and scanning electron microscopy revealed their shape. MSCs were treated with different concentrations of AuNPs to assess biocompatibility. The results indicated that 1.25 and 2.5 ppm concentrations of AuNPs significantly enhanced MSC proliferation, reduced reactive oxygen species generation, and attenuated platelet/monocyte activation. Furthermore, the presence of filopodia and lamellipodia suggested improved adhesion ability of MSCs when incubated with 1.25 and 2.5 ppm AuNPs. The expression of matrix metalloproteinase (MMP-2/9) was also upregulated under these concentrations, indicating enhanced cell migration ability. Lower levels of apoptosis were observed in MSCs treated with 1.25 and 2.5 ppm AuNPs compared to higher concentrations, as assessed by Annexin-V/PI double staining and Fluorescence Activated Cell Sorting (FACS). Western blotting analysis showed increased expression of anti-apoptotic proteins Cyclin-D1 and Bcl-2. Additionally, real-time PCR analysis demonstrated reduced expression of inflammatory cytokines (TNF-α, IL-1β, IFN-γ, IL-6, and IL-8) in MSCs treated with 1.25 and 2.5 ppm AuNPs. Animal model tests revealed that these concentrations of AuNPs exhibited better biocompatibility, including anti-inflammatory effects and endothelialization. Overall, 1.25 and 2.5 ppm AuNP solutions were shown to enhance the biological functions of MSCs, suggesting their potential as biocompatible nanomedicine for regenerative research.
CCRG-06. PP2A DEFICIENCY INDUCES CELLULAR SENESCENCE AND SENSITIZES P53 MUTANT TUMORS TO SENOLYTIC THERAPY
Authors: Isha Mondal, Oishika Das, Rongze Olivia Lu, Winson Ho
Journal: Neuro-Oncology (2023)

Abstract Loss of p53 can promote tumor progression by preventing induction of senescence, a critical tumor-suppressive mechanism that limits tumor proliferation. Promotion of senescence in a p53-independent manner can be a novel strategy to overcome treatment resistance in p53-mutant brain tumors. Protein-Phosphatase-2A (PP2A), a ubiquitous serine/threonine phosphatase, regulates various cellular processes including cell-cycle progression. We hypothesize that PP2A-deficiency can induce tumor senescence independent of p53-mutational-status and sensitize tumors to senolytic therapy. CRISPR-KO of PP2A was generated in multiple p53-mutant tumor cell lines: D425 (human medulloblastoma), SB28 and GL261 (murine glioma). Hallmarks of senescence such as b-galactosidase, p21, and p16 were assessed via flow cytometry, RT-PCR and Western-Blot. Secretion of senescence-associated secretory phenotype (SASP), such as IL8, was assessed through ELISA. b-galactosidase, p21, p16 and IL8 were dramatically increased in PP2A-KO compared to WT at baseline. The effect was further enhanced when combined with radiation therapy (RT), a known inducer of senescence, demonstrating PP2A-deficiency synergizes with RT and significantly increases cellular senescence. Expression of CD1d, a MHC1-like molecule associated with senescence and required for invariant NKT cell-activation (iNKT), was dramatically increased in PP2A-KO in comparison to WT via flow-cytometry. In-vitro, sensitivity to WT and PP2A-KO cells to senolytic treatments, such as ABT-737 and iNKT-cell therapy, was tested using an XCelligence-assay system and flow-cytometry-based cytotoxicity assay. PP2A-deficient cells were sensitized to ABT-737, a BCL-xL inhibitor that preferentially targets and kills senescent cells. Co-culture revealed increased cytotoxicity of iNKT-cells against PP2A-deficient tumors compared to WT. In vivo, D425 WT or PP2A-KO cells were injected intracranially into nude NU/J mice, radiated 2 days post-injection, and monitored till endpoint. At baseline, PP2A-KO mice survived longer than WT, and those with PP2A-KO and RT survived the longest. In conclusion, we report that PP2A-deficiency in tumor cells can induce p53-independent senescence and sensitize brain tumors to senolytic therapy.
RADT-50. EVIDENCE-BASED MULTIVARIATE NORMAL TISSUE COMPLICATION PROBABILITY (NTCP) STUDY OF DOMAIN-SPECIFIC COGNITIVE DECLINE AFTER PARTIAL BRAIN RADIATION (RT)
Authors: Austin Hopper, Michael Connor, Mia Salans, Roshan Karunamuni, Soumya Unnikrishnan, Minh Huynh-Le, Michelle Tibbs, Anny Reyes, Alena Stasenko, Carrie McDonald, Vitali Moiseenko, Issam El-Naqa, Jona Hattangandi-Gluth
Journal: Neuro-Oncology (2023)

Abstract Beyond the hippocampus, there are no evidence-based dose constraints for eloquent brain structures which subserve cognitive domains. We performed a multivariate NTCP analysis of post-RT neurocognitive decline, examining dosimetric predictors of eloquent brain regions in a prospective longitudinal clinical trial. 83 patients with primary brain tumors receiving fractionated RT completed comprehensive neurocognitive evaluation and high-resolution volumetric and diffusion MRI at baseline and 6 months post-RT. Image processing using robust, validated automated segmentation parcellated individual white matter (WM) tracts, cortical regions, and hippocampi. Well-validated neurocognitive tests evaluating multiple cognitive domains were assessed with negative reliable change indices adjusted for practice effects between timepoints scored as decline. Univariate logistic regression and multivariate model building were performed examining dose to eloquent structures and clinical variables. Univariate analysis showed mean dose to the bilateral caudal anterior cingulate cortex and WM were correlated with decline in executive function. Attention/processing speed decline was correlated with mean/max dose to the posterior corpus callosum (CC), volume getting &amp;gt;20 Gy in the combined CC, as well as anti-epileptic use and chemotherapy. On multivariate analysis for attention automated bootstrapped logistic regression performance at nested cross-validation by AUC was 0.59 (0.54-0.65); LASSO model performance by AUC was 0.60 (0.54-0.66) with mean dose to combined CC being the most frequent variable in both. The top three most important variables in Random Forest by mean decrease in Gini coefficient were max dose to posterior and combined CC and mean dose to anterior CC. Model performance by AUC was 0.70 (0.64-0.75). Here we present the first, to our knowledge, NTCP model for decline in attention/processing speed, along with dosimetric predictors of executive function decline. We found that after partial brain RT, dose to several ROIs significantly correlated with post-RT impairment. These data can guide future cognitive-sparing strategies for brain RT.
CTNI-46. UPFRONT VERSUS DEFERRED TREATMENT IN LOWER GRADE IDH-MUTANT GLIOMAS: A SINGLE-CENTER RETROSPECTIVE ANALYSIS
Authors: Anuj Patel, Benjamin Whitfield, Leomar Ballester, Vinay Puduvalli, Carlos Kamiya-Matsuoka
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND IDH-mutant gliomas are a diverse group of gliomas possessing a mutation in the isocitrate dehydrogenase enzyme. The treatment for both oligodendroglioma (1p/19q co-deleted) and astrocytoma includes resection followed by radiation therapy and chemotherapy. However, there is debate over the optimal timing of adjuvant treatment after surgery. An initial observation approach is sometimes pursued, particularly after gross total resection in young adults. We sought to examine the impact of timing of treatment in order to inform clinical decision-making. METHODS We identified 286 biopsied or resected glial tumors treated at MD Anderson Cancer Center from July 2015 to June 2022. Tumors were categorized using available molecular data based on the WHO 2021 diagnostic criteria. Progression-free survival was analyzed using Kaplan-Meier estimates. RESULTS Of 286 tumors, 232 had identified IDH-mutation, of which 89 were 1p/19q co-deleted and 143 were non-co-deleted. Of oligodendroglioma patients, 71 received either upfront chemotherapy, radiation or both and 18 received treatment upon progression; of astrocytoma patients, 96 were treated upfront and 47 received treatment at progression. Among oligodendroglioma patients, there were no significant differences in PFS between treatment timing groups (75.6 vs 66.7 months, P = 0.18). There was additionally no difference between oligodendroglioma patients treated initially with PC or PCV regimens vs temozolomide (not reached vs 75.4 months, P = 0.24). Among astrocytoma patients, upfront treatment was associated with longer PFS (93.8 vs 45.2 months, P &amp;lt; 0.01). Patients with low-risk grade 2 gliomas (age &amp;lt;40 and gross total resection) also showed longer PFS with upfront treatment (138.0 vs 45.2 months, P = 0.03). CONCLUSION Overall, the results in this molecularly defined cohort suggest a progression-free survival benefit from upfront treatment in IDH-mutant lower grade gliomas, including in low-risk gliomas. The optimal timing and nature of adjuvant treatment for lower grade gliomas remains a matter of debate.
DDDR-14. DEVELOPMENT OF A NOVEL CYP17A1-TARGETED INHIBITOR FOR GLIOBLASTOMA
Authors: Hsien-Chung Chen, Tsung-I Hsu
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is a highly aggressive and invasive brain tumor, resistant to current standard treatments, including temozolomide (TMZ) and radiotherapy. Despite these interventions, GBM's intrinsic drug resistance often renders it incurable, thus highlighting the dire need for novel therapeutic strategies. In this study, we used ultra-high pressure liquid chromatography-mass spectrometry to examine the levels of neurosteroids in tumor specimens from primary and recurrent GBM patients. This led to the discovery of differential expression patterns, most notably in androgen, including dehydroepiandrosterone and testosterone. Our results indicated androgen over-production weakens the GBM's sensitivity to TMZ by inducing post-translational modification of Sp1 protein, which aids in DNA repair. Interestingly, Sp1 activity is further enhanced by histone deacetylase (HDAC) 6, which in turn diminishes the DNA damage caused by TMZ. In addition, proteomic analysis revealed an overexpression of cytochrome (CYP) 17A1, particularly in recurrent GBM, which led us to hypothesize that a drug inhibiting both CYP17A1 and HDAC6 could potentially serve as a viable treatment for TMZ-resistant GBM. To validate this, the drug was tested in vitro on U87MG-R cells and patient-derived Pt#3 TMZ-resistant cells, demonstrating the therapeutic efficacy based on cell viability assays. In vivo testing in the TMZ-resistant GBM orthotopic mouse model also showed promising anti-tumor activity, with treated mice demonstrating increased survival times compared to controls. In conclusion, our findings suggest that this drug targeting both CYP17A1 and HDAC6 presents a potential breakthrough in GBM-targeted therapy, addressing the pervasive issue of TMZ resistance.
EOLP-07. A REAL-WORLD INTEGRATED OUTPATIENT PALLIATIVE AND SUPPORTIVE CARE CLINIC IN A REGIONAL COMMUNITY NEURO-ONCOLOGY PRACTICE
Authors: Dominique Celestino, Deepna Chand, Keith Robert-Quinn, Minhdan Nguyen, Judy Truong, Jared Chow, Emmaline Mauritson, Naveed Wagle, Jose Carrillo, Tiffany Juarez, Garni Barkhoudarian, Santosh Kesari, Akanksha Sharma
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Palliative care (PC), a specialty focused on alleviating suffering, is appropriate at any stage of serious illness and can improve quality of life, survival and reduce care partner distress. Integration within the care of neuro-oncology (NOC) patients remains difficult. At our center, patients who might benefit from specialty palliative care have been seen by a dual fellowship trained NOC and PC specialist (A.S.) since February 2021. We present our experience here. METHODS This was a retrospective chart review including records from the electronic medical record system from February 2021 to May 2023. RESULTS/ CONCLUSION A total of 58 patients received integrated PC from 651 seen in the general NOC practice. The most common diagnosis was glioma (59%), with the rest being a mixture of lymphoma or systemic cancer with brain involvement. Majority of patients were male (53%) and identified as White/Caucasian (86%). The average age of patients at referral was 58. The most common focus was symptom management (40%), followed by guidance around decision-making (14%), care partner support (11%), advance care planning (10%), and support with coping (9%). The most common symptoms discussed included fatigue (36%), seizures (22%), and pain (21%). By the submission of this abstract, 28 (48%) patients had passed away, 22 of whom (79%) had formally enrolled on hospice with an average of 24 days prior to death. The primary cause of death was respiratory failure towards end of life (71%). Three patients (11%) had chosen to employ the California End of Life Act. Advanced directives were discussed and completed in 82% and a proxy had been identified in 100%. This model of integrated PC for NOC clinics appears to be feasible, meaningful and is welcomed for it allows focused, dedicated attention to symptom management, distress alleviation, advance care planning and hospice transition.